Abstract 1149
Background
Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. Whether and how the pyruvate kinase M2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity of gastrointestinal cancer is unknown.
Methods
One duodenal cancer cell line AZ521, and two gastric cancer cell lines NUGC and SCM-1 and were treated with OSU-A9 which is known to induce cytotoxicity of acute myeloid leukemia through ROS generation. The in vitro cytotoxic and proapoptotic activities of OSU-A9 was evaluated by the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay and annexin V – propidium iodide staining, respectively. Overexpression experiment was performed by transfection with indicated plasmid using Lipofectamine 2000 according to the manufacturer’s protocol.
Results
OSU-A9 induced a dose- and time-dependent cytotoxicity and apoptosis in duodenal cancer and gastric cancer cells through ROS generation. The IC50 of OSU-A9 at 24 and 48 h for AZ-521, NUGC and SCM-1 were 2.68 and 1.83, 3.34 and 2.81, and 2.71 and 2.36 mM, respectively. Pretreatment with ROS scavenger rescued the cancer cells from apoptosis and concomitant PARP cleavage, implicating a key role of ROS in OSU-A9-induced cell death. Furthermore, OSU-A9-mediated ROS down-regulated pTyr105-PKM2 which occurred in cell nucleus rather than in cytoplasm. Ectopic overexpression of PKM-2 partially overcame the cytotoxicity of OSU-A9, which implied a role of phosphorylated PKM2 beyond glycolysis in survival of duodenal cancer and gastric cancer cells.
Conclusions
This study shows that ROS-mediated intranuclear PKM2 dephosphorylation, in part, contributes to the anticancer activity of OSU-A9 in duodenal cancer and gastric cancer. Differential down-regulation of phosphorylated PKM2 between nucleus and cytoplasm suggests a non-glycolytic role of PKM2 in cell survival response to ROS stress.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The Ministry of Health and Welfare, Taiwan.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5437 - Salivary cytokines and oral mucosa cells apoptosis in patients during hematopoietic cell transplantation: possible relationship with oral mucositis
Presenter: Luciana Corrêa
Session: Poster Display session 1
Resources:
Abstract
1483 - A randomized trial of sodium alginate prevention of radiation-induced esophagitis in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy: OLCSG1401
Presenter: Toshihide Yokoyama
Session: Poster Display session 1
Resources:
Abstract
2047 - Taste and smell alterations (TSAs) in patients (pts) with stage II-III colon cancer (CC): a pilot within the PROTECT study
Presenter: Jeroen Derksen
Session: Poster Display session 1
Resources:
Abstract
5984 - Clinical characteristics are associated with acupuncture treatment response for xerostomia in cancer patients
Presenter: Wenli Liu
Session: Poster Display session 1
Resources:
Abstract
2845 - Psychosocial Distress of Adolescent and Young Adults with Cancer at Diagnosis: A Case-Matched Retrospective Cohort of 2045 Patients in British Columbia.
Presenter: Alannah Smrke
Session: Poster Display session 1
Resources:
Abstract
724 - Accuracy of distress thermometer to measure cancer-related mood disorders in Chinese patients with cancer
Presenter: Sudip Thapa
Session: Poster Display session 1
Resources:
Abstract
2357 - Modalities of biosimilar filgrastim use in clinical practice in >1000 patients receiving chemotherapy regimens with a rest period of ≤14 days: the TOPAZE study
Presenter: Jean Marc Phelip
Session: Poster Display session 1
Resources:
Abstract
1426 - The Effect of Increasing Doses of Pegfilgrastim (Peg) on Thrombocytopenia (T) in Breast Cancer (BC) Patients (pts) Receiving Taxotere (Doc), Doxorubicin, Cyclophosphamide (TAC) and Plinabulin (Plin)
Presenter: Douglas Blayney
Session: Poster Display session 1
Resources:
Abstract
712 - The use of intravenous ferric carboxymaltose without erythropoiesis-stimulating agents in the treatment of anemia in cancer patients undergoing chemotherapy with or without radiotherapy
Presenter: Hikmat Abdel-Razeq
Session: Poster Display session 1
Resources:
Abstract
1496 - Randomized, double-blind, cross-over Phase I study comparing pharmacokinetics, pharmacodynamics, safety and immunogenicity of a biosimilar pegfilgrastim with EU and US references
Presenter: Maria Velinova
Session: Poster Display session 1
Resources:
Abstract